Research Interests

The Molecular Evolution of Proteins and Viruses

The ability to rapidly evolve to escape host immunity and adapt to new selection pressures is a defining feature of many of the most medically problematic viral diseases, including influenza. While this rapid evolution is bad from the perspective of public health, it offers a unique vantage from which to study immunology and evolutionary biology. We are entering an era where it is possible to track the detailed changes that occur when a virus jumps between species, is transferred between members of the same species, or is subjected to varying pressures within an individual. My lab uses a combination of experimental and computational approaches to analyze and interpret the evolution of influenza. Specific areas of interest include the following:The molecular evolution of proteins and viruses
The ability to rapidly evolve to escape host immunity and adapt to new selection pressures is a defining feature of many of the most medically problematic viral diseases, including influenza. While this rapid evolution is bad from the perspective of public health, it offers a unique vantage from which to study immunology and evolutionary biology. We are entering an era where it is possible to track the detailed changes that occur when a virus jumps between species, is transferred between members of the same species, or is subjected to varying pressures within an individual. My lab uses a combination of experimental and computational approaches to analyze and interpret the evolution of influenza. Specific areas of interest include the following:

The role of epistasis in molecular evolution

Stephen Jay Gould famously argued for the role of contingency in evolution, claiming that evolutionary histories were highly dependent on initial historical accidents. At the molecular level, contingency can arise through epistasis, the phenomenon whereby one mutation alters the impact of subsequent mutations. Influenza provides a unique system for studying epistasis, since we can trace the virus’s natural evolution over much of the last century in step-by-step detail. We are experimentally reconstructing such evolutionary trajectories to determine how early mutations influence the effects of subsequent ones through epistatic interactions. Our preliminary results suggest that immune escape mutations are especially likely to epistatically interact with prior buffering mutations, raising the tantalizing possibility that it might be possible to identify mutations that foreshadow future antigenic change.

Influenza has undergone repeated transfers among a variety of hosts, including birds, humans, pigs, horses, and dogs. Existing sequence databases extensively chronicle viral change after these host transfers. We apply computational techniques to these sequences to identify mutations and patterns that are under differential selection in these hosts. We then use experiments to identify the specific host factors driving this differential viral evolution. The goal of this research is to use natural virus evolution as a probe of the innate immune system.

Defining the physical constraints on influenza evolution

Influenza’s rapid evolution has thus far made it impossible to create a single universal vaccine against all strains. However, there are reasons to believe that the virus’s capacity for antigenic evolution does have limits. Portions of influenza are highly conserved, and broadly effective vaccines have been created against other error-prone RNA viruses such as polio and measles. We are using a combination of structural biology and next-generation sequencing of mutant libraries to define the physical constraints on influenza’s capacity for evolutionary change. Our long-term goal is to develop a deeper understanding of the physical properties that underpin viral evolvability, and to apply this understanding to design therapeutics that are more resistant to evolutionary escape.